MOLECULAR AND CLINICAL ONCOLOGY 14: 56, 2021

The predictive factor for pathological downgrading after in patients with Gleason score 4+3 or 4+4 cancer

YOICHIRO TOHI, IORI MATSUDA, KENGO FUJIWARA, SATOSHI HARADA, AYAKO ITO, MARI YAMASAKI, YASUYUKI MIYAUCHI, YUKI MATSUOKA, TAKUMA KATO, RIKIYA TAOKA, HIROYUKI TSUNEMORI, NOBUFUMI UEDA and MIKIO SUGIMOTO

Department of , Faculty of Medicine, Kagawa University, Miki‑cho, Kita‑gun, Kagawa 761‑0793, Japan

Received September 29, 2020; Accepted December 9, 2020

DOI: 10.3892/mco.2021.2218

Abstract. The proportion of Gleason pattern (GP) 4 prostate positive core with the highest GS were lower in the downgrade cancers at prostate biopsy has a clinically significant impact group than in the no downgrade group (45 vs. 66.7%, P=0.025; on risk stratification for patients with . In 20 vs. 30%, P=0.048, respectively). When performing pathological diagnosis including GP 4, a biopsy Gleason multivariate logistic regression analysis, the only significant score (GS) of 3+4 has a more favorable prognosis than a GS predictor for downgrade was lower percentage of highest GS of 4+3 and 4+4. However, the discrepancy between biopsy and cores out of positive biopsy cores (odds ratio, 2.469; 95% confi‑ prostatectomy specimens is well known. The current study dence interval, 1.029‑5.925 P=0.043). In conclusion, patients investigated the clinical parameters and biopsy specimens with biopsy GS 4+4 and 4+3 often exhibit a downgrade to GS associated with pathological downgrading after prostatectomy 3+4 or less in prostatectomy specimens. The lower percentage in with a GS of 4+3 or 4+4 prostate cancer. A total of of highest GS cores out of positive biopsy cores was associated 302 patients with prostate cancer who underwent robot‑assisted with downgrade. radical prostatectomy between August 2013 and May 2019 were retrospectively reviewed. A total of 103 patients had Introduction biopsies with GSs of 4+3 and GS 4+4 (unfavorable pathology). The proportion of patients who were downgraded from The clinical impact of the proportion of Gleason pattern (GP) 4 unfavorable disease to GS ≤3+4 (favorable pathology) in prostate cancers in prostate biopsy is very significant in terms of prostatectomy specimens was investigated. Logistic regression risk stratification for patients with prostate cancer. Risk strati‑ analysis was used to explore the association between clinical fication varies from low risk to high risk depending on whether parameters and downgrading in prostatectomy specimens. GP 4 is adopted. Furthermore, the same intermediate‑risk A total of 43 patients (41.7%) were downgraded from biopsy Gleason score (GS) 3+4 and GS 4+3 have very different onco‑ GS to prostatectomy GS. The proportions of downgrade in logical prognoses (1,2). The National Comprehensive Cancer biopsy GS 4+4 and 4+3 were 14.6 and 27.1%, respectively. Network Clinical Practice Guidelines divide the risk between The percentage of highest GS out of positive biopsy cores GS 3+4 and GS 4+3 (3). In addition, GS 4+3 and GS 4+4 had and the maximum percentage of cancer involvement within a a similar oncological prognosis (1). In other words, a wide range of risk is assessed, from favorable intermediate to high risk, based on the percentage of GP4 in the prostate biopsy specimen. In clinical practice, risk classification is used to determine the course of treatment. Correspondence to: Dr Yoichiro Tohi, Department of Urology, Currently, in the diagnosis of prostate cancer, the highest Faculty of Medicine, Kagawa University, 1750‑1 Ikenobe, Miki‑cho, biopsy GS is used to assess risk in order to avoid underestima‑ Kita‑gun, Kagawa 761‑0793, Japan tion in biopsy pathology. There are many reports of differences E‑mail: [email protected] between prostate biopsy specimens and prostatectomy speci‑ mens (4,5). Therefore, adopting the highest biopsy GS could Abbreviations: GP, Gleason pattern; GS, Gleason score; RALP, robot‑assisted laparoscopic radical prostatectomy; PSA, be overestimated while ensuring safety. Upgrading from prostate‑specific antigen; ORs, odds ratios; CIs, confidence intervals; biopsy GS to prostatectomy GS is often reported as a focus IQR, interquartile range for differences between biopsy specimens and prostatectomy specimens (6‑8). On the other hand, there are few reports of Key words: biopsy, Gleason score, prostate cancer, prostatectomy, downgrading from biopsy GS to prostatectomy GS (9‑11). downgrading biopsy, Gleason In this context, the downgrade has significant implications in patients with biopsy GP 4, who could be assessed by a wide range of risk. Identifying factors that could contribute 2 TOHI et al: PATHOLOGICAL DOWNGRADE POST-PROSTATECTOMY IN PATIENTS WITH BIOPSY GLEASON SCORE 4+3/4+4 to downgrading prior to treatment would be of great benefit results of logistic regression analyses are presented as odds in clinical practice because patients could be provided with a ratios (ORs), 95% confidence intervals (CIs) and P‑values. A safer guarantee than expected by biopsy GS. P‑value <0.05 was considered to indicate statistical signifi‑ Therefore, we aimed to investigate the factors of clinical cance. All statistical analyses were performed using SPSS for parameters and biopsy specimens associated with down‑ Windows (version 25.0; IBM Corp.). grading in prostatectomy specimens in patients with biopsy GS 4+3 or GS 4+4 prostate cancer. Results

Materials and methods A total of 122 patients with prostate cancer had the highest biopsy GS 4+3 and GS 4+4. Patients who received neoadju‑ Ethics statements. The current study was approved by the vant hormonal therapy (n=6) and had a Gleason pattern 5 in Institutional Review Board of Kagawa University (admission any biopsy core (n=2), diagnostic PSA level ≥20 ng/ml (n=3), no. 2020‑074). The need for informed consent was waived clinical T stage ≥cT3 (n=7), and both diagnostic PSA level given the retrospective nature of the study, but information of ≥20 ng/ml and clinical T stage ≥cT3 (n=1) were excluded. this study was disclosed on the website and opportunities for Finally, 103 patients met the inclusion criteria for this study. refusal were guaranteed. Table I shows the baseline characteristics of patients. Fifty‑two patients (50.5%) had biopsy GS 4+3, and 51 patients (49.5%) Study design and patient population. We performed a retro‑ had biopsy GS 4+4. The median percentage of positive cores spective analysis of 302 patients with prostate cancer who out of all biopsy cores was 25% [interquartile range (IQR), underwent robot‑assisted laparoscopic radical prostatectomy 15‑36.6]. The median percentage of highest GS cores out of (RALP) at local hospital from August 2013 to May 2019. positive biopsy cores was 30% (IQR, 10‑47.5). The median Patients were included in this study if the biopsy highest GS maximum percentage of cancer involvement within a posi‑ was GS 4+3 and GS 4+4 and RALP was performed. Patients tive core with the highest GS was 50% (IQR, 33.3‑100). The were excluded if there was no evidence of nodal or distant median follow‑up time was 36 months (IQR, 12‑54.5). metastases on preoperative imaging, Gleason pattern 5 was Table II shows the relationship between biopsy and radical present in any biopsy cores, neoadjuvant hormonal therapy prostatectomy GS. Of note, 41.7% of the patients were down‑ was used, prior radiation therapy was performed, the diag‑ graded from biopsy GS to radical prostatectomy GS. In detail, nostic prostate‑specific antigen (PSA) level was ≥20 ng/ml, or the percentages of downgrade were 14.6 and 27.1% in biopsy cancer was clinical stage ≥cT3. GS 4+4 and biopsy GS 4+3, respectively. Table III shows the association of characteristics downgraded from biopsy GS to Definitions. GS ≤3+4 was defined as favorable pathology, and radical prostatectomy GS. The percentage of highest GS cores GS 4+3 and GS 4+4 were defined as unfavorable pathology. out of positive biopsy cores and the maximum percentage of Downgrading was defined as unfavorable pathology at biopsy cancer involvement within a positive core with the highest to favorable pathology at radical prostatectomy. If a higher GS were lower in the downgrade group than in the no down‑ tertiary pattern was present in prostatectomy specimens, it grade group [45 vs. 66.7%, P=0.025; 20 vs. 30%, P=0.048, was listed as ‘+ T’ in the GS. A tertiary pattern of the same respectively]. The PSA level at diagnosis (6.4 vs. 6.23 ng/ml, Gleason score was not considered grade classification (e.g., P=0.973), PSA density (0.23 vs. 0.26 ng/ml/cc, P=0.409), biopsy GS 4+4 to prostatectomy GS 3+4+T was considered a clinical T stage (P=0.361), and percent of positive cores out of downgrade). all biopsy cores (25 vs. 25%, P=0.939) were not significantly Most of the biopsies (76.8%) were performed at outside different between the groups. On multivariate logistic regres‑ institutions, but all biopsy specimens were reviewed at our sion analysis, the only significant predictor for downgrade was institution before RALP. lower percentage of highest GS cores out of positive biopsy cores (OR: 2.469; 95% CI 1.029‑5.925, P=0.043) (Table IV). Data collection and statistical analysis. All data were collected from electronic medical records. In the present study, Discussion baseline characteristics (age, PSA level at diagnosis, PSA density, prostate volume, clinical T‑stage, biopsy GS, number We demonstrated that 41% of patients with biopsy GS 4+4 of biopsy cores, number of positive biopsy cores, percentage of or GS 4+3 were downgraded to GS ≤3+4 at radical prosta‑ positive cores out of all biopsy cores, percentage of highest GS tectomy, and this number could not be ignored. This result cores out of positive biopsy cores, and maximum percentage indicates that some patients with biopsy GS 4+4 or GS 4+3 are of cancer involvement within a positive core with the highest often overestimated. In addition, we showed that the predictor GS) were collected retrospectively. We divided the patients of downgrading was lower percentage of highest GS cores out into two groups: The downgrade group from biopsy GS 4+4 of positive biopsy cores. or 4+3 to GS ≤3+4 at radical prostatectomy and no downgrade There are few reports of downgrading from biopsy GS group, and compared baseline characteristics between the two to prostatectomy GS, all of which focused on patients with groups, using the chi‑square and Fisher exact test for categor‑ biopsy GS 4+4 (9‑11). Ginsburg et al reported that 59% ical variables, and the Mann‑Whitney U test for continuous were downgraded to GS ≤7 at prostatectomy, and ≤2 biopsy variables. Logistic regression analyses were performed to cores of GS 4+4, ≤50% maximal tumor involvement of the assess the prediction of GS downgrading after radical pros‑ cores demonstrating GS 4+4, and the presence of GP 3 in tatectomy in patients with biopsy GS 4+3 and GS 4+4. The separate biopsy cores was associated with downgrading, from MOLECULAR AND CLINICAL ONCOLOGY 14: 56, 2021 3

Table I. Patient baseline demographics and pathological outcomes.

Variable Value

Median age, years (IQR) 69 (64.5‑72.0) Median PSA level at diagnosis, ng/ml (IQR) 6.3 (4.93‑8.64) Median PSA density, ng/ml/cc (IQR) 0.25 (0.17‑0.38) Median prostate volume, cc (IQR) 27 (20.5‑31.9) Number of biopsy cores, n (IQR) 12 (12‑14) Number of positive biopsy cores, n (IQR) 3 (2‑5) Percent of positive cores out of all biopsy cores, median % (IQR) 25 (15.0‑36.6) Percent of highest Gleason score cores out of positive biopsy cores, median % (IQR) 30 (10.0‑47.5) Maximum percent of cancer involvement within a positive core with highest Gleason scores, 50 (33.3‑100.0) median % (IQR) Biopsy Gleason score, n (%) 4+3 52 (50.5) 4+4 51 (49.5) Clinical stage, n (%) T1c 13 (12.6) T2a 79 (76.7) T2b 6 (5.8) T2c 5 (4.9) Median follow‑up, months (IQR) 36 (12.0‑54.5)

Table II. Radical prostatectomy Gleason score stratified by biopsy Gleason score.

Radical prostatectomy Gleason Score, n (%) Biopsy Gleason ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑-‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ score HGPIN 3+3 3+4 3+4+T 4+3 4+3+T 3+5 4+4 4+4+T 9‑10 Total

4+3 0 (0.0) 1 (1.9) 26 (50.0) 1 (1.9) 14 (27.0) 6 (11.5) 0 (0) 4 (7.7) 0 (0.0) 0 (0.0) 52 4+4 1 (2.0) 0 (0) 13 (25.5) 1 (2.0) 17 (33.3) 7 (13.7) 0 (0) 7 (13.7) 2 (3.9) 3 (5.9) 51

T, tertiary pattern 5; HGPIN, high‑grade prostatic intraepithelial neoplasia.

a retrospective review of biopsy GS 4+4 (9). Gansler et al we showed that a lower percentage of highest GS cores out also reported that 60% of biopsy GS8 were downgraded to of positive biopsy cores was associated with downgrading GS ≤7 at prostatectomy, and downgrading was associated in prostatectomy specimens. This result of the downgrade with decreasing age, African American race, lower clinical factor is easy to understand because it almost matches what T stage, lower PSA level, and the combination of primary and we believe to be the case in our clinical practice. Our results secondary GS (3+5 greater than 4+4 greater than 5+3) (10). support the possibility of oversampling small lesions of GP 4 Qi et al reported that 61.5% of biopsy GS 8 were downgraded cancer. Because of the diagnosis of its small lesions, GP 4 may on prostatectomy, and the predictive factors of downgrading be missed by pathological examination of the prostatectomy were lower PSA level at biopsy, number of GS 8 biopsy cores, specimens, or may be accidentally sampled in the biopsy. and the presence of GP 3 on biopsy cores (11). With regard The overestimation of risk stratification may sometimes lead to biopsy GS 8, a large discrepancy between biopsy GS and to overtreatment. High‑risk prostate cancers are aggressively prostatectomy GS was observed. treated. In radiation therapy for prostate cancer, the duration The novelty of our study was that we included an analysis of androgen deprivation therapy at high risk is longer than that of downgrading in biopsy GS 4+3 patients and defined at other risk (12,13). The longer term of androgen deprivation ‘downgrade’ as ‘to GS ≤3+4 at prostatectomy’. We changed therapy is attributable to osteoporosis, metabolic syndrome, the subject and the definition of downgrading from previous diabetes mellitus, cardiovascular events, and a decline in reports because GS 4+3 and GS 4+4 had a similar oncological quality of life (14). In addition, downgrading to GS 3+4 or prognosis (1), and GS ≥4+3 had a significantly poorer prognosis lower means that active surveillance, a strategy to avoid compared to GS 3+4 (2‑3). In our study, the incidence of down‑ overtreatment, may be a potential option in some cases (15). grading from biopsy to prostatectomy was 41%. Additionally, In other words, identifying the factors to downgrade prior to 4 TOHI et al: PATHOLOGICAL DOWNGRADE POST-PROSTATECTOMY IN PATIENTS WITH BIOPSY GLEASON SCORE 4+3/4+4

Table III. Association of characteristics downgraded from biopsy Gleason score 4+4 or 4+3 to ≤3+4 at radical prostatectomy.

Variable Downgrade No downgrade P‑value

Patients, n 42 61 Median age, year (IQR) 69.5 (65‑72) 69 (63‑72) 0.965 Median PSA level at diagnosis, ng/ml (IQR) 6.4 (5.00‑8.07) 6.23 (4.89‑8.90) 0.973 Median PSA density, ng/ml/cc (IQR) 0.23 (0.16‑0.35) 0.26 (0.18‑0.39) 0.409 Median prostate volume, cc (IQR) 28 (21.0‑31.3) 26 (20‑32) 0.552 Number of biopsy cores, n (IQR) 12 (12‑14) 12 (12‑14) 0.442 Percent of positive cores out of all biopsy cores, % (IQR) 25 (16.7‑35.1) 25 (15.0‑37.5) 0.939 Percent of highest Gleason score cores out of positive biopsy cores, % (IQR) 45 (30.8‑66.7) 66.7 (40‑100) 0.025 ≤55, n (%) 30 (71.4) 29 (47.5) >55, n (%) 12 (28.6) 32 (52.5) Maximum percent of cancer involvement within a positive core with highest 20 (10.0‑37.5) 30 (20‑50) 0.048 Gleason scores, % (IQR) ≤27.5, n (%) 25 (59.5) 24 (39.3) >27.5, n (%) 17 (40.5) 37 (60.7) Clinical T stage, n (%) 0.361 T1c 7 (16.7) 6 (9.8) T2a 31 (73.8) 48 (78.7) T2b 1 (2.4) 5 (8.2) T2c 3 (7.1) 2 (3.3)

Table IV. Multivariate models for the prediction of Gleason score downgrading after radical prostatectomy in patients with biopsy a Gleason score of 4+3 and 4+4.

Multivariate ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑-‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ Variable OR 95% CI P‑value

Age at diagnosis 0.989 (0.915‑1.069) 0.786 PSA level 0.990 (0.869‑1.127) 0.880 Percent of highest Gleason score cores out of positive biopsy cores ≤55% 2.469 (1.029‑5.925) 0.043 Maximum percent of cancer involvement within a positive core with highest 1.786 (0.740‑4.309) 0.197 Gleason scores ≤27.5% Clinical T stage: T1c (reference) T2a 0.599 (0.169‑2.131) 0.429 T2b 0.196 (0.016‑2.397) 0.202 T2c 1.055 (0.111‑10.012) 0.963

treatment could contribute to a wider range for less invasive and characterization of prostate cancer (16). In this context, treatment options. Furthermore, our findings of the prediction MRI could contribute to filling this diagnostic gap. Regarding of downgrading from biopsy to prostatectomy specimens have the upgrading from biopsy to prostatectomy specimens, important implications for providing treatment while ensuring Alqahtani et al evaluated whether MRI has the potential to safety. Patients with downgrading may have a more favorable narrow the discrepancy of histopathological grades between prognosis after prostatectomy than expected by biopsy GS. biopsy and radical prostatectomy, using the data of 102 patients Previous studies have reported discrepancies between with localized prostate cancer at a single institution (17). The prostate biopsy specimens and prostatectomy specimens (4,5). report showed that the PIRADS v2.0 score was associated with We presume the discrepancy between biopsy and prosta‑ postoperative GS upgrading and created a nomogram for GS tectomy GS is largely due to the difference in diagnostic upgrading prediction. However, prostate cancer is a popular procedures. In biopsy pathology, the highest biopsy GS is disease and may be diagnosed at any institution, although not used to avoid underestimation. Currently, pre‑biopsy magnetic all institutions have MRI. In this respect, our results may help resonance imaging (MRI) has shown promise in the detection fill this diagnostic gap. MOLECULAR AND CLINICAL ONCOLOGY 14: 56, 2021 5

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